This research award will support the development of Christine M. Burt Solorzano, M.D., of the University of Virginia (UVA), as she continues to train in patient-oriented research under the mentorship of John C. Marshall, M.D., Ph.D., an established investigator in reproductive neuroendocrinology and the polycystic ovary syndrome (PCOS). Dr. Solorzano is a pediatric endocrinologist with previous research experience focusing on aspects of obesity. Her immediate goal is to understand the origins of PCOS and identify new treatment strategies. Her long-term goal is to become a leader in pediatric PCOS research, assessing the efficacy of interventions to prevent PCOS. This training will allow Dr. Solorzano to acquire skills needed to become an independent clinical investigator. The application outlines a career development plan that includes comprehensive instruction in clinical trials methodology, biostatistics, epidemiology, research ethics, assay methodology, and study design, partly via a Masters of Clinical Research. Dr. Solorzano's research proposal is designed to determine the source and timing of androgen excess in overweight girls and to identify potential strategies to reduce androgen production in this population. Androgen excess during puberty is a forerunner to PCOS-a common chronic endocrine disorder associated with infertility, metabolic disorders, and hirsutism in women. Childhood obesity - an international problem -puts girls at risk for androgen excess, even in early puberty. Identifying sources of androgen excess during puberty is needed to elucidate targets for preventing PCOS. Women and older adolescents with PCOS have predominantly ovarian overproduction of androgens. However, it is unknown whether the adrenal gland, ovary, or both are responsible for androgen excess in overweight girls prior to developing the full PCOS syndrome. This is especially true during early puberty when ovarian function is thought to be minimal. Aim 1 will use adrenal suppression/stimulation testing and ovarian stimulation testing to examine sources of androgen production in normal and overweight girls throughout puberty. Aim 2 will use low-dose hydrocortisone and leuprolide therapy to test whether short-term suppression of adrenocorticotropin or gonadotropin production can reduce androgen levels in overweight girls with androgen excess. Aim 3 will examine the potential efficacy of longer-term therapies (e.g., low-dose hydrocortisone, metformin, or spironolactone) to reduce obesity-related androgen excess in girls during all stages of puberty. The research will be performed in the Clinical Research Center at UVA and would extend diagnostic tools to examine adrenal and ovarian androgen production to young girls. It may identify targets for therapeutic strategies to treat or prevent androgen excess during puberty - a critical stage for the development of PCOS. PUBLIC HEALTH RELEVANCE: Childhood obesity - an international problem - puts girls at risk for excess male hormone (androgen) production and polycystic ovary syndrome (PCOS). PCOS leads to infertility, metabolic problems, and male-pattern hair growth in women and adolescents. This project would identify sources of obesity-related androgen excess during puberty and examine the efficacy of potential therapies in reducing androgen levels in girls during all stages of puberty, with the goal of preventing PCOS.